The incidence of cocaine-related sudden deaths has reached epidemic proportions in many metropolitan areas around the United States. Widespread cocaine abuse is associated with significant neuropsychiatric and CNS complications. Epidemiological analysis of cocaine-related deaths in Dade County, Florida, has revealed a number of important findings regarding the temporal trends and associated risk factors. The epidemiological findings indicate that only 6 to 11 % of the cocaine overdose cases had significant underlying coronary artery disease or ventricular hypertrophy, suggesting that these cardiovascular risk factors may account for only a subgroup of the cocaine-related sudden deaths. High dose cocaine toxicity is associated with seizures. However, the percentage of cocaine-related deaths with seizures has declined during the epidemic. This observation is consistent with toxicology findings which demonstrate that median plasma concentrations of cocaine associated with sudden death have declined annually. In contrast, an increased incidence of cocaine psychosis and sudden death-has been reported which closely follows the epidemic curve for cocaine-related deaths in Dade County. The epidemiological analysis of all cocaine overdose deaths (1971 to the present) provides a basis for assigning cocaine overdose deaths into three subgroups: high dose acute toxicity (seizures); low dose toxicity without significant underlying cardiac pathology; and cocaine-related death in subjects exhibiting preterminal excited delirium. Guided by this analysis, an extensive catalogue of well-characterized postmortem neuropathological specimens is available for the proposed study of the morphological and neurochemical consequences of cocaine abuse in the human brain. Cocaine has prominent reinforcing and subjective effects that contribute to its pattern of abuse. An increase in CNS dopamine neurotransmission, resulting from the blockade of dopamine uptake and mediated by the activation of dopamine receptors, is a primary determinant of the reinforcing effects of cocaine. Recent advances in molecular biology have allowed the cloning and characterization of the main molecular components involved in dopaminergic synaptic transmission. By combining immunological and molecular biological techniques, highly specific antibodies to the dopa:nine transporter and receptor subtypes have been made available using fusion proteins as antigens. We plan to use these monospecific antibody probes to characterize changes in the molecularly-defined proteins of the dopaminergic synapse in the human brain postmortem from cocaine overdose deaths. Defining the adaptive responses of dopaminergic synaptic proteins to repeated cocaine use may help to pinpoint the pharmacological sites in human brain which mediate behavioral tolerance and sensitization and to identify the neural substrates that play a role in dose escalation and subsequent toxicity.